Recently, a transdermal therapeutic system (TTS) for treatment or prevention of disease through transdermal absorption of drug has become recognized as one drug delivery system (DDS). In TTS, not only drug for local action but also drug administration expected for systemic action has been tried, and some have already been a commercial reality.
Transdermal preparations can evade, for example, first-pass drug metabolism in liver and various adverse reactions and, in addition, enable long-term and sustainable drug administration. Among them, an adhesive patch that contains a drug in an adhesive has been considerably developed as facilitating drug administration and enabling strict dose control.
An adhesive patch generally includes a support formed of a woven fabric, a nonwoven fabric, a plastic film or the like and, as laminated on the support, a drug-containing adhesive layer, and generally in a form of having a release liner laminated on the adhesive layer, it is kept in a package formed of a package material of a resin film or the like, and provided to user.
As one characteristic feature thereof, a recent tendency toward adhesive patches is that a soft and velvety adhesive layer, for example, an adhesive layer containing a large quantity of a liquid component held therein is employed therein for the purpose of enhancing the soft touch of the patch in sticking to skin, or for the purpose of reducing skin irritation to be caused by horny layer removal in peeling the patch, or for the purpose of increasing the solubility and the skin permeability of the drug in the adhesive layer. In such adhesive patches, “cold flow”, or that is, oozing out or sticking out of the adhesive layer component from the exposed area of the adhesive layer of the adhesive patch becomes a problem.
Cold flow occurs depending on the characteristics of the adhesive layer, and often occurs during long-term storage in a state where a load is given to adhesive patches for a long period of time, or that is, in a state where an adhesive patch is packed in a package.
When cold flow occurs in an adhesive patch, the drug may flow out along with the adhesive layer component from the exposed area of the adhesive layer of the adhesive patch and, as a result, the amount of the drug contained in the adhesive patch may reduce, therefore unfavorably resulting in drug efficacy reduction. In addition, the adhesive layer component having oozed out or stuck out may adhere to the inner face of the package, therefore causing negative influences on the adhesive patch in that the adhesive patch could be poorly taken out of the package and that the adhesive patch may peel off or may get dirty during wear to skin. Further, in case where the adhesive layer is thick, the tendency is remarkable since the amount of the adhesive layer component is large. Accordingly, in adhesive patches, it is desirable that cold flow hardly occurs and the adhesive layer can sustain its original shape.
Against the above-mentioned problems, Patent Reference 1 discloses a technique for a skin adhesive material, in which the thickness of the skin adhesive layer positioned at the middle part of the support film is controlled to fall within a range of from 0.2 mm to 0.5 mm and the peripheral part thereof is pressed to reduce the thickness of the skin adhesive layer to 0.05 mm to 0.2 mm, thereby preventing the skin adhesive layer from sticking out from the edges of the skin adhesive material and preventing the edges of the skin adhesive material from peeling away.
More precisely, the method for producing the skin adhesive material described in Patent Reference 1 is characterized in that a skin adhesive layer is formed on a release sheet and a support film is laminated thereon, and the resulting laminate sheet is blanked in two stages, wherein after the first-stage blanking, the pressing to form the thin peripheral part is carried out without heating. Namely, in case where the laminate sheet is first pressed and thereafter blanked into the final shape in one stage, the skin adhesive layer positioned between the support film and the release sheet could hardly move to both sides in pressing, and even if the layer could move, it could not have an escape route, and therefore the part of the skin adhesive layer adjacent to the peripheral part may rise by pressing. Therefore, for evading the formation of the rise, the method described in Patent Reference 1 is characterized in that the previous blanking into a larger size is followed by the pressing so as to extrude the skin adhesive layer adjacent to the peripheral part from the blanked edges and the second-stage blanking gives the final shape.
However, regarding the skin adhesive material described in Patent Reference 1, during storage thereof in a package, the opportunity for the exposed part of the adhesive layer such as the edges of the skin adhesive material to be in contact with the inner surface of the package could not be reduced sufficiently, and therefore, in case where the skin adhesive layer has oozed out or stuck out from the exposed part of the adhesive layer of the skin adhesive material in the package, the adhesion of the skin adhesive material to the inner surface of the package could not be sufficiently prevented and, as a result, the skin adhesive material could hardly be taken out of the package. In addition, when the skin adhesive material could be brought into contact with clothes and others while kept stuck to skin, the opportunity for the edges of the skin adhesive material to be rubbed against the clothes and others could not be fully reduced, and the edges of the skin adhesive material may peel off. Further, since the skin adhesive layer in the peripheral part is thin, the adhesive power thereof to skin in the peripheral part may lower as compared with that in the middle part.
In particular, in an adhesive patch that contains a drug liquid at room temperature, not only cold flow of the adhesive layer components but also a phenomenon of drug oozing from the adhesive layer during long-term storage occur, whereby the drug content in the adhesive patch may lower to cause a risk of drug efficacy reduction.
As another case of developing an adhesive patch, Patent Reference 2 relates to an adhesive patch-containing package bag in which the adhesive patch containing bisoprolol or a salt thereof in the adhesive layer thereof can be stored stably, and it discloses that, when the relative humidity inside the package bag is at most 25%, then the stability of bisoprolol or a salt thereof becomes excellent. However, the patent reference does not describe anything relating to oozing of bisoprolol or a salt thereof in the package bag and relating to the influence of cold flow of the adhesive layer component on the stability, the handleability and the adhesiveness of the adhesive patch, and much more nothing is investigated therein relating to the shape of the adhesive patch for solving the problems.